Methods of treating RBP4 related diseases with triazolopyridines

ABSTRACT

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for the treatment of retinal binding protein (RBP4) related diseases, such as obesity and the like.

CROSS-REFERENCE

This application is a divisional of U.S. application Ser. No. 16/008,838filed Jun. 14, 2018 which claims the benefit of U.S. provisional patentapplication No. 62/520,420 filed on Jun. 15, 2017, which is incorporatedherein by reference in its entirety.

BACKGROUND

A need exists in the medicinal arts for the effective treatment ofmetabolic diseases and disorders associated with retinol-binding protein4 (RBP4).

BRIEF SUMMARY OF THE INVENTION

Provided herein are methods for the treatment of obesity, diabetes,non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis withheterocyclic derivative compounds and pharmaceutical compositionsthereof.

Some embodiments provided herein describe methods of treating ametabolic disease or disorder in a subject in need thereof, the methodcomprising administering to the subject a composition comprising atherapeutically effective amount of a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof:

-   -   wherein:        -   each R¹ is independently halogen, haloalkyl, or alkyl;        -   R² is —H, —OH, or halogen;        -   p is 0, 1, 2, 3, 4, or 5:        -   A has the structure:

-   -   wherein:        -   α, β, χ, and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, C₁-C₄ alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

In some embodiments of a compound of Formula (I), when α is present,then Z₁ and Z₂ are N, X is N, β is present, and χ and δ are absent.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), A has the structure

-   -   wherein:        -   n is 0, 1, or 2;        -   α, β, χ, δ, ε, and ϕ are each independently absent or            present, and when present each is a bond;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N or NR³,            -   wherein R¹ is H, C₁-C₄ alkyl, or oxetane;        -   X is N;        -   Y₁, Y₂, Y₃ and each occurrence of Y₄ are each independently            CR⁴, C(R⁵)₂, NR⁶, O, N, SO₂, or —(C═O)—, wherein:            -   each R⁴ is independently H, halogen, C₁-C₁₀ alkyl,                C₁-C₁₀ cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH,                —C(O)O(C₁-C₁₀ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl),                —C(O)N(C₁-C₄ alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl),                —NHC(O)N(C₁-C₄ alkyl)₂, —SO₂NH(C₁-C₁₀ alkyl),                —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF₃;            -   each R⁵ is independently H or C₁-C₁₀ alkyl, and            -   each R⁶ is independently H, C₁-C₁₀ alkyl, C₃-C₆                cycloalkyl, —(C₁-C₁₀ alkyl)-CF₃, —(C₁-C₁₀ alkyl)OCH₃,                —(C₁-C₁₀ alkyl)-halogen, —SO₂(C₁-C₁₀ alkyl), —SO₂(C₁-C₁₀                alkyl)-CF₃, —SO₂(C₁-C₁₀ alkyl)OCH₃, —SO₂(C₁-C₁₀                alkyl)-halogen, —C(O)(C₁-C₁₀ alkyl), —C(O)(C₁-C₁₀                alkyl)CF₃, —C(O)(C₁-C₁₀ alkyl)OCH₃, —C(O)(C₁-C₁₀                alkyl)-halogen, —C(O)NH(C₁-C₁₀ alkyl), —C(O)N(C₁-C₁₀                alkyl)₂, —(C₁-C₁₀ alkyl)C(O)OH, —C(O)NH₂, or oxetane

In some embodiments of a compound of Formula (I), when α is present,then Z₁ and Z₂ are N, X is N, β is present, and χ and δ are absent; whenε and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃, and Y₄, areindependently —CR⁴— or N; or when ε and ϕ are each absent, then n=0, 1or 2, each of Y₁, Y₂, Y₃, and each occurrence of Y₄ are independentlyC(R⁵)₂, NR⁶, O, or SO₂.

In some embodiments of a compound of Formula (I), where in α, β, ε, andϕ are present; χ and δ are absent; Z₁ is N; Z₂ is N; and X is N.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I),

A has the structure:

-   -   wherein:        -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₄ or N; and            -   each R¹ is independently H, halogen, C₁-C₁₀ alkyl,                C₁-C₁₀ cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH,                —C(O)O(C₁-C₁₀ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl),                —C(O)N(C₁-C₄ alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl),                —NHC(O)N(C₁-C₄ alkyl)₂, —SO₂NH(C₁-C₁₀ alkyl),                —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF₃.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), A has the structure:

-   -   wherein:        -   each R₄ is independently H, halogen, C₁-C₄ alkyl, C₃-C₆            cycloalkyl, —O(C₁-C₄ alkyl), —CN, —CF₃, —C(O)OH, —C(O)NH₂,            —C(O)N(CH₃)₂, —C(O)NHCH₃, or —NHC(O)N(CH₃)₂.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of formula (I), each R¹ is independentlyF, Br, Cl, C₁₋₆ haloalkyl, or C₁₋₆ alkyl.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), wherein each R¹ isindependently F or CF₃.

One embodiment provides a method of treating a metabolic disease ordisorder in a subject in need thereof, the method comprisingadministering to the subject a composition comprising a therapeuticallyeffective amount of a compound having the structure:

-   -   or a pharmaceutically acceptable salt, solvate, polymorph,        prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

One embodiment provides a method of treating a metabolic disease ordisorder in a subject in need thereof, the method comprisingadministering to the subject a composition comprising a therapeuticallyeffective amount of a compound having the structure:

-   -   or a pharmaceutically acceptable salt, solvate, polymorph,        prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments, the metabolic disease or disorder is obesity, type1 diabetes, diabetic retinopathy, non-alcoholic fatty liver disease(NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, livercancer, or liver cirrhosis.

In some embodiments, the therapeutically effective amount of a compoundof Formula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is about25 mg per day, about 50 mg per day, about 75 mg per day, about 100 mgper day, about 150 mg per day, about 200 mg per day, or about 400 mg perday.

In some embodiments, the therapeutically effective amount of a compoundof Formula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is about50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mgper day, or about 400 mg per day. In some embodiments, thetherapeutically effective amount of a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is up to 25 mg perday, up to 50 mg per day, up to 75 mg per day, up to 100 mg per day, upto 150 mg per day, up to 200 mg per day, up to 400 mg per day, up to 600mg per day, up to 800 mg per day, or up to 1000 mg per day. In someembodiments, the therapeutically effective amount of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is up to400 mg per day.

In some embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 50% from baseline. Insome embodiments, 24 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 65% from baseline. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 80% from baseline. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite. N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In some, 24hours after administration of a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

In some embodiments, the disease or disorder is obesity. In someembodiments, the disease or disorder is type II diabetes. In someembodiments, the disease or disorder is non-proliferative diabeticretinopathy (NPDR) or proliferative diabetic retinopathy (PDR). In someembodiments, the disease or disorder is a liver disease. In someembodiments, the disease or disorder is non-alcoholic fatty liverdisease (NAFLD). In some embodiments, the disease or disorder isnon-alcoholic steatohepatitis (NASH). In some embodiments, the diseaseor disorder is liver fibrosis. In some embodiments, the disease ordisorder is liver cirrhosis. In some embodiments, the disease ordisorder is liver cancer.

In some embodiments of a method of treating a metabolic disorder, thecompound is administered to the subject orally or intravenously. Incertain embodiments, the compound of Formula (I) is administered orally.In certain embodiments, the compound of Formula (I) is administeredintravenously. In some embodiments, the administration is to treat anexisting disease or disorder. In some embodiments, the administration isprovided as prophylaxis.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates absolute values of RBP4 plasma levels in male SpragueDawley rats following a single intravenous dose of Compound 1 at 2mg/kg.

FIG. 2 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male Sprague Dawley rats following a singleintravenous dose of Compound 1 at 2 mg/kg.

FIG. 3 illustrates absolute values of RBP4 plasma levels in male SpragueDawley rats following a single oral dose of Compound 1 at 5 mg/kg.

FIG. 4 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male Sprague Dawley rats following a single oraldose of Compound 1 at 5 mg/kg.

FIG. 5 illustrates Compound 1 plasma levels in male Sprague Dawley ratsfollowing a single intravenous dose of 2 mg/kg.

FIG. 6 illustrates Compound 1 plasma levels in male Sprague Dawley ratsfollowing a single oral dose of 5 mg/kg.

FIG. 7 illustrates absolute values of RBP4 plasma levels in male micefollowing a single intravenous dose of Compound 1 at 2 mg/kg.

FIG. 8 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male mice following a single intravenous dose ofCompound 1 at 2 mg/kg.

FIG. 9 illustrates absolute values of RBP4 plasma levels in male micefollowing a single oral dose of Compound 1 at 5 mg/kg.

FIG. 10 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male mice following a single oral dose of Compound1 at 5 mg/kg.

FIG. 11 illustrates Compound 1 plasma levels in male mice following asingle intravenous dose of 2 mg/kg.

FIG. 12 illustrates Compound 1 plasma levels in male mice following asingle oral dose of 5 mg/kg.

FIG. 13 illustrates absolute values of RBP4 plasma levels in male beagledogs following a single intravenous dose of Compound 1 at 0.5 mg/kg.

FIG. 14 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male beagle dogs following a single intravenousdose of Compound 1 at 0.5 mg/kg.

FIG. 15 illustrates absolute values of RBP4 plasma levels in male beagledogs following a single oral dose of Compound 1 at 2 mg/kg.

FIG. 16 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male beagle dogs following a single oral dose ofCompound 1 at 2 mg/kg.

FIG. 17 illustrates Compound 1 plasma levels in male beagle dogsfollowing a single intravenous dose of 0.5 mg/kg.

FIG. 18 illustrates Compound 1 plasma levels in male beagle dogsfollowing a single oral dose of 2 mg/kg.

FIG. 19 illustrates absolute values of RBP4 plasma levels in maleSprague Dawley rats following a single intravenous dose of Compound 2 at1 or 2 mg/kg. Rat 1M3 died at compound injection, and rat 1M1 was dosedat 1 mg/kg.

FIG. 20 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male Sprague Dawley rats following a singleintravenous dose of Compound 2 at 1 or 2 mg/kg.

FIG. 21 illustrates absolute values of RBP4 serum levels in male SpragueDawley rats following a single oral dose of Compound 2 at 5 mg/kg.

FIG. 22 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male Sprague Dawley rats following a single oraldose of Compound 2 at 5 mg/kg.

FIG. 23 illustrates Compound 2 plasma levels in male Sprague Dawley ratsfollowing a single intravenous dose of 1 or 2 mg/kg.

FIG. 24 illustrates Compound 2 plasma levels in male Sprague Dawley ratsfollowing a single oral dose of 5 mg/kg.

FIG. 25 illustrates absolute values of RBP4 plasma levels in male micefollowing a single intravenous dose of Compound 2 at 2 mg/kg.

FIG. 26 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male mice following a single intravenous dose ofCompound 2 at 2 mg/kg.

FIG. 27 illustrates absolute values of RBP4 plasma levels in male micefollowing a single oral dose of Compound 2 at 5 mg/kg.

FIG. 28 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male mice following a single oral dose of Compound2 at 5 mg/kg.

FIG. 29 illustrates Compound 2 plasma levels in male mice following asingle intravenous dose of 2 mg/kg.

FIG. 30 illustrates the percent reduction of RBP4 plasma levels comparedto pre-dose levels in male mice following a single intravenous dose ofCompound 2 at 2 mg/kg.

FIG. 31 illustrates Compound 2 plasma levels in male mice following asingle oral dose of 5 mg/kg.

FIG. 32A illustrates a preventative dosing schedule wherein Compound 2treatment is initiated at the same time as a western high fat diet(HFD).

FIG. 32B illustrates a treatment dosing schedule wherein Compound 2 orobeticholic acid (OCA) treatment is initiated after a conditioningperiod on a western high fat diet (HFD).

FIG. 33A illustrates RBP4 plasma levels in ob/ob mice following apreventative dosing schedule with Compound 2 at 25 mg/kg.

FIG. 33B illustrates RBP4 plasma levels in ob/ob mice following atreatment (after conditioning on a western high fat diet) dosingschedule with Compound 2 (50 mg/kg) or obeticholic acid (OCA, 30 mg/kg).

FIG. 34A illustrates glucose levels in ob/ob mice following apreventative dosing schedule with Compound 2.

FIG. 34B illustrates area under curve glucose levels in ob/ob micefollowing a preventative dosing schedule with Compound 2.

FIG. 35A illustrates glucose levels in ob/ob mice following a treatment(after conditioning on a western high fat diet) dosing schedule withCompound 2 or obeticholic acid (OCA).

FIG. 35B illustrates terminal insulin levels in ob/ob mice following atreatment (after conditioning on a western high fat diet) dosingschedule with Compound 2 or obeticholic acid (OCA).

FIG. 36 illustrates a Western blot analysis of RBP4 levels in adiposetissue of ob/ob mice on a preventative dosing schedule wherein Compound2 treatment is initiated at the same time as a western high fat diet(HFD), relative to an untreated control (vehicle).

FIG. 37 illustrates NASH scores in ob/ob mice on a HFD after treatmentwith Compound 2.

FIG. 38A illustrates a liver tissue section in ob/ob mice on a HFD aftertreatment with a control.

FIG. 38B illustrates a liver tissue section in ob/ob mice on a HFD aftertreatment with Compound 2.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange, in some instances, will vary between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) is not intendedto exclude that in other certain embodiments, for example, an embodimentof any composition of matter, composition, method, or process, or thelike, described herein, “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl comprises two to six carbonatoms. In other embodiments, an alkynyl comprises two to four carbonatoms. The alkynyl is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from to twelve cone to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupare through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond, and having from two to twelve carbon atoms.The alkenylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkenylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkenylene). In other embodiments, an alkenylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkenylene). In other embodiments, analkenylene comprises two to four carbon atoms (e.g., C₂-C₄ alkenylene).In other embodiments, an alkenylene comprises two to three carbon atoms(e.g., C₂-C₃ alkenylene). In other embodiments, an alkenylene comprisesfive to eight carbon atoms (e.g., C₅-C₈ alkenylene). In otherembodiments, an alkenylene comprises two to five carbon atoms (e.g.,C₂-C₅ alkenylene). In other embodiments, an alkenylene comprises threeto five carbon atoms (e.g., C₃-C₅ alkenylene). Unless stated otherwisespecifically in the specification, an alkenylene chain is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atom (e.g., C₂ alkylene). In other embodiments, an alkynylenecomprises five to eight carbon atoms (e.g., C₅-C₈ alkynylene). In otherembodiments, an alkynylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkynylene). Unless stated otherwise specifically in thespecification, an alkynylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)t-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is saturated (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b-)N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical are optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkynylene chain as defined above.The alkynylene chain and the carbocyclyl radical are optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical areoptionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolin yl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, structures depicted herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C— or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)]2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commercially from chemicalvendors, such as Aldrich Chemical Co.

Deuterium-transfer reagents suitable for use in nucleophilicsubstitution reactions, such as iodomethane-d₃ (CD₃I), are readilyavailable and may be employed to transfer a deuterium-substituted carbonatom under nucleophilic substitution reaction conditions to the reactionsubstrate. The use of CD₃I is illustrated, by way of example only, inthe reaction schemes below.

Deuterium-transfer reagents, such as lithium aluminum deuteride(LiAlD₄), are employed to transfer deuterium under reducing conditionsto the reaction substrate. The use of LiAlD₄ is illustrated, by way ofexample only, in the reaction schemes below.

Deuterium gas and palladium catalyst are employed to reduce unsaturatedcarbon-carbon linkages and to perform a reductive substitution of arylcarbon-halogen bonds as illustrated, by way of example only, in thereaction schemes below.

In one embodiment, the compounds disclosed herein contain one deuteriumatom. In another embodiment, the compounds disclosed herein contain twodeuterium atoms. In another embodiment, the compounds disclosed hereincontain three deuterium atoms. In another embodiment, the compoundsdisclosed herein contain four deuterium atoms. In another embodiment,the compounds disclosed herein contain five deuterium atoms. In anotherembodiment, the compounds disclosed herein contain six deuterium atoms.In another embodiment, the compounds disclosed herein contain more thansix deuterium atoms. In another embodiment, the compound disclosedherein is fully substituted with deuterium atoms and contains nonon-exchangeable ¹H hydrogen atoms. In one embodiment, the level ofdeuterium incorporation is determined by synthetic methods in which adeuterated synthetic building block is used as a starting material.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the heterocyclicRBP4 inhibitory compounds described herein is intended to encompass anyand all pharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and, aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are, in some embodiments,administered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease has not been made.

“Prodrug” is meant to indicate a compound that is, in some embodiments,converted under physiological conditions or by solvolysis to abiologically active compound described herein. Thus, the term “prodrug”refers to a precursor of a biologically active compound that ispharmaceutically acceptable. A prodrug is typically inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, are prepared by modifying functional groups present inthe active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

RBP4 Inhibitory Compounds

Provided herein in some embodiments are RBP4 inhibitory compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for inhibiting RPB4 and for thetreatment of metabolic diseases or disorders, such as NASH, NAFLD, typeII diabetes, diabetic retinopathy, obesity, fibrosis, cirrhosis, orhepatocellular carcinoma.

Some embodiments provided herein describe a compound, or apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisornerl or isomer thereof, for use intreating a metabolic disease or disorder, having the structure ofFormula (I):

-   -   wherein:        -   each R¹ is independently halogen, optionally substituted            alkyl, optionally substituted cycloalkyl, optionally            substituted heterocyclyl, optionally substituted            heterocyclalkyl, —COR⁷, —CON(R⁷)₂, optionally substituted            (C₀-C₄ alkylene)-CN, optionally substituted (C₀-C₄            alkylene)-OR⁷, optionally substituted (C₀-C₄            alkylene)-N(R⁷)₂, optionally substituted (C₀-C₄            alkylene)N(R⁸)—COR⁷, optionally substituted (C₀-C₄            alkylene)-SO₂N(R⁷)₂, optionally substituted (C₀-C₄            alkylene)-SO₂R⁷, optionally substituted (C₀-C₄            alkylene)N(R⁸)—SO₂N(R⁷)₂, or optionally substituted (C₀-C₄            alkylene)N(R⁸)—SO₂R⁷;            -   each R⁷ is independently selected from H, optionally                substituted alkyl, optionally substituted alkenyl,                optionally substituted carbocyclyl, optionally                substituted carbocyclylalkyl, optionally substituted                aryl, optionally substituted aralkyl, optionally                substituted heterocyclyl, optionally substituted                heterocyclylalkyl, optionally substituted heteroaryl, or                optionally substituted heteroarylalkyl; or two R¹¹                groups together with the nitrogen to which they are                attached join to form an optionally substituted                N-heterocyclyl;        -   each R⁸ is independently selected from H or optionally            substituted alkyl;        -   R² is H, —OH, optionally substituted alkyl, or halogen;        -   p is 0, 1, 2, 3, 4, or 5;    -   A has the structure:

-   -   wherein:        -   α, β, χ, and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, optionally substituted alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

Some embodiments provided herein describe a compound, or apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, having thestructure of Formula (I) wherein:

-   -   each R¹ is independently halogen, optionally substituted C₁₋₆        alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally        substituted C₂₋₆ heterocyclyl, optionally substituted C₃₋₁₀ to        heterocyclalkyl, —COR⁷, —CON(R⁷)₂, optionally substituted (C₀-C₄        alkylene)-CN, optionally substituted (C₀-C₄ alkylene)-OR⁷,        optionally substituted (C₀-C₄ alkylene)-N(R⁸)₂, optionally        substituted (C₀-C₄ alkylene)N(R⁸)—COR⁷, optionally substituted        (C₀-C₄ alkylene)-SO₂N(R⁷)₂, optionally substituted (C₀-C₄        alkylene)-SO₂R⁷, optionally substituted (C₀-C₄        alkylene)N(R⁸)—SO₂N(R⁷)₂, or optionally substituted (C₀-C₄        alkylene)N(R⁸)—SO₂R⁷;        -   each R⁷ is independently selected from H, optionally            substituted C₁₋₆ alkyl, optionally substituted C₃₋₆            carbocyclyl, optionally substituted C₃₋₁₀ carbocyclylalkyl,            optionally substituted C₂₋₆ heterocyclyl, optionally            substituted C₂₋₁₀ heterocyclylalkyl; or two R¹¹ groups            together with the nitrogen to which they are attached join            to form an optionally substituted C₂₋₆ N-heterocyclyl;        -   each R⁸ is independently selected from H or optionally            substituted C₁₋₆ alkyl;    -   R² is —H, —OH, optionally substituted C₁₋₆ alkyl, or halogen;    -   p is 0, 1, 2, 3, 4, or 5    -   A has the structure:

-   -   wherein:        -   α, β, χ, and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, optionally substituted C₁₋₆ alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

Certain embodiments provided herein describe a compound, or apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, having thestructure of Formula (I) wherein:

-   -   each R¹ is independently halogen. C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₁₋₆ cycloalkyl, C₂₋₆ heterocyclyl, C₃₋₁₀ heterocyclalkyl,        —COR⁷, —CON(R⁷)₂, (C₀-C₄ alkylene)-CN, (C₀-C₄ alkylene)-OR⁷,        (C₀-C₄ alkylene)-N(R⁷)₂, (C₀-C₄ alkylene)N(R⁸)—COR⁷, (C₀-C₄        alkylene)-SO₂N(R⁷)₂, (C₀-C₄ alkylene)-SO₂R⁷, (C₀-C₄        alkylene)N(R⁸)—SO₂N(R⁷)₂, or (C₀-C₄ alkylene)N(R⁸)—SO₂R⁷;        -   each R⁷ is independently selected from H, C₁₋₆ alkyl, C₃₋₆            carbocyclyl, C₃₋₁₀ to carbocyclylalkyl, C₂₋₆ heterocyclyl,            C₂₋₁₀ to heterocyclylalkyl; or two R¹¹ groups together with            the nitrogen to which they are attached join to form a C₂₋₆            N-heterocyclyl;        -   each R⁸ is independently selected from H or C₁₋₆ alkyl;    -   R² is —H, —OH, C₁₋₆, alkyl, or halogen;    -   p is 0, 1, 2, 3, 4, or 5;    -   A has the structure:

-   -   wherein:        -   α, β, χ and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, C₁₋₆ alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

Some embodiments provided herein describe a compound, or apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, having thestructure of Formula (I) wherein:

-   -   each R¹ is independently halogen, haloalkyl, or alkyl;    -   R² is —H, —OH, or halogen;    -   p is 0, 1, 2, 3, 4, or 5;    -   A has the structure:

-   -   wherein:        -   α, β, χ and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, C₁-C₄ alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

Certain embodiments provided herein describe a compound, or apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite. N-oxide, stereoisomer, or isomer thereof, having thestructure of Formula (I) wherein:

-   -   each R¹ is independently Br, Cl, F, C₁₋₆ fluoroalkyl, or C₁₋₆        alkyl;    -   R² is —H, —OH, Br, Cl, or F;    -   p is 0, 1, 2, 3, 4, or 5;    -   A has the structure:

-   -   wherein:        -   α, β, χ and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, C₁-C₄ alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

Certain embodiments provided herein describe a compound, or apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, having thestructure of Formula (I) wherein:

-   -   each R¹ is independently F or CF₃;    -   R² is —H;    -   p is 1 or 2;    -   A has the structure:

-   -   wherein:        -   α, β, χ and δ are each independently absent or present, and            when present each is a bond;        -   X is N;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N, or NR³;        -   R³ is H, C₁-C₄ alkyl, or oxetane; and        -   B is a substituted or unsubstituted fused 5-, 6-, or            7-membered ring structure.

For any and all of the embodiments of Formula (I), substituents areselected from among a subset of the listed alternatives.

In some embodiments, each R¹ is independently halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted C₂₋₆ heterocyclyl, optionally substituted C₃₋₁₀heterocyclalkyl, —COR⁷, —CON(R⁷)₂, optionally substituted (C₀-C₄alkylene)-CN, optionally substituted (C₀-C₄ alkylene)-OR⁷, optionallysubstituted (C₀-C₄ alkylene)-N(R⁷)₂, optionally substituted (C₀-C₄alkylene)N(R⁸)—COR⁷, optionally substituted (C₀-C₄ alkylene)-SO₂N(R⁷)₂,optionally substituted (C₀-C₄ alkylene)-SO₂R⁷, optionally substituted(C₀-C₄ alkylene)N(R⁸)—SO₂N(R⁷)₂, or optionally substituted (C₀-C₄alkylene)N(R⁸)—SO₂R⁷. In certain embodiments, each R¹ is independentlyhalogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl,C₃₋₁₀ heterocyclalkyl, —COR⁷, —CON(R⁷)₂, (C₀-C₄ alkylene)-CN, (C₀-C₄alkylene)-OR⁷, (C₀-C₄ alkylene)-N(R⁷)₂, (C₀-C₄ alkylene)N(R⁸)—COR⁷,(C₀-C₄ alkylene)-SO₂N(R⁷)₂, (C₀-C₄ alkylene)-SO₂R⁷, (C₀-C₄alkylene)N(R⁸)—SO₂N(R⁷)₂, or (C₀-C₄ alkylene)N(R⁸)—SO₂R⁷. In someembodiments, each R¹ is independently halogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, —COR⁷, —CON(R⁷)₂, (C₀-C₄ alkylene)-CN, (C₀-C₄ alkylene)-OR⁷,or (C₀-C₄ alkylene)-N(R⁷)₂. In other embodiments, each R¹ isindependently (C₀-C₄ alkylene)N(R⁷)—COR⁷, (C₀-C₄ alkylene)-SO₂N(R⁷)₂,(C₀-C₄ alkylene)-SO₂R⁷, (C₀-C₄ alkylene)N(R⁸)—SO₂N(R⁷)₂, or (C₀-C₄alkylene)N(R⁸)—SO₂R⁷. In some embodiments, each R¹ is independentlyhalogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —COR⁷, —CON(R⁷)₂, —CN, (C₀-C₄alkylene)-OR⁷, or (C₀-C₄ alkylene)-N(R⁷)₂. In some embodiments, each R¹is independently halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or —CN. In certainembodiments, each R¹ is independently F, Br, Cl, C₁₋₆ haloalkyl, or C₁₋₆alkyl. In specific embodiments, each R¹ is independently F or CF₃.

In some embodiments, each R⁷ is independently selected from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆carbocyclyl, optionally substituted C₃₋₁₀ carbocyclylalkyl, optionallysubstituted C₂₋₆ heterocyclyl, optionally substituted C₂₋₁₀heterocyclylalkyl; or two R¹¹ groups together with the nitrogen to whichthey are attached join to form an optionally substituted C₂₋₆N-heterocyclyl. In some embodiments, each R⁷ is independently selectedfrom H, C₁₋₆, alkyl, C₃₋₆ carbocyclyl, C₃₋₁₀ carbocyclylalkyl, C₂₋₆heterocyclyl, C₂₋₁₀ heterocyclylalkyl; or two R¹¹ groups together withthe nitrogen to which they are attached join to form a C₂₋₆N-heterocyclyl. In some embodiments, each R⁷ is independently selectedfrom H, C₁₋₆ alkyl, or C₂₋₆ carbocyclyl. In certain embodiments, two R¹¹groups together with the nitrogen to which they are attached join toform an optionally substituted C₂₋₆ N-heterocyclyl. In some embodiments,each R⁷ is independently selected from H or C₁₋₆ alkyl. In someembodiments, each R⁷ is H or Me.

In some embodiments, each R⁸ is independently selected from H, C₁₋₄alkyl, or C₁₋₆ haloalkyl. In some embodiments, each R⁸ is independentlyselected from H or C₁₋₆ alkyl. In some embodiments, each R⁸ isindependently selected from H or Me. In some embodiments, each R⁸ is H.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0,1, 2, or 3. In some embodiments, p is 0, 1 or 2. In some embodiments, pis 0 or 1. In some embodiments, p is 1, 2, or 3. In some embodiments, pis 1 or 2. In some embodiments, p is 1, 2, 3, or 4. In some embodiments,p is 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments,p is 0. In some embodiments, p is 1. In some embodiments, p is 2 In someembodiments, p is 3 In some embodiments, p is 4. In some embodiments, pis 5. In some embodiments, p is 1.

In some embodiments, R¹ is —H, —OH, optionally substituted alkyl, orhalogen. In some embodiments, R² is —H, —OH, alkyl, haloalkyl, orhalogen. In some embodiments, R² is —H, —OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or halogen. In some embodiments, R² is —H, —OH, Me, CF₃, or halogen. Insome embodiments, R² is —H, —OH, Me, CF₃, Cl, or F. In some embodiments,R² is —H, —OH, Me, CF₃, or F. In some embodiments, R² is —H, —OH, orhalogen. In some embodiments, R² is —H, —OH, or F. In some embodiments,R² is —H. In some embodiments, R² is —OH. In some embodiments, R² is F.In some embodiments, R² is Cl.

In some embodiments, α is present. In some embodiments, Z₁ and Z₂ are N.In some embodiments, β is present. In some embodiments, χ and δ areabsent. In certain embodiments, α is present; Z₁ and Z₂ are N; X is N; βis present; and χ and δ are absent.

In some embodiments, A has the structure:

-   -   wherein:        -   n is 0, 1, or 2;        -   α, β, χ, δ, ε, and ϕ are each independently absent or            present, and when present each is a bond;        -   Z₁ is S, O, or N;        -   Z₂ is S, O, N or NR³,        -   wherein R³ is H, C₁-C₄ alkyl, or oxetane;        -   X is N;        -   Y₁, Y₂, Y₃ and each occurrence of Y₄ are each independently            CR⁴, C(R⁵)₂, NR⁶, O, N, SO₂, or —(C═O)—, wherein:            -   each R⁴ is independently H, halogen, C₁-C₁₀ alkyl,                C₁-C₁₀ cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH,                —C(O)O(C₁-C₁₀ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl),                —C(O)N(C₁-C₄ alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl),                —NHC(O)N(C₁-C₄ alkyl)₂, —SO₂NH(C₁-C₁₀ alkyl),                —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or C₁-C₁₀ haloalkyl;            -   each R⁵ is independently H or C₁-C₁₀ alkyl, and            -   each R¹ is independently H, C₁-C₁₀ alkyl, C₃-C₆                cycloalkyl, —(C₁-C₁₀ alkyl)CF₃, —(C₁-C₁₀ alkyl)OCH₃,                —(C₁-C₁₀ alkyl)-halogen, —SO₂(C₁-C₁₀ alkyl), —SO₂(C₁-C₁₀                alkyl)-CF₃, —SO₂(C₁-C₁₀ alkyl)OCH₃, —SO₂(C₁-C₁₀                alkyl)-halogen, —C(O)(C₁-C₁₀ alkyl), —C(O)(C₁-C₁₀                alkyl)CF₃, —C(O)(C₁-C₁₀ alkyl)OCH₃, —C(O)(C₁-C₁₀                alkyl)-halogen, —C(O)NH(C₁-C₁₀, alkyl), —C(O)N(C₁-C₁₀                alkyl)₂, —(C₁-C₁₀ alkyl)C(O)OH, —C(O)NH₂, or oxetane.

In some embodiments, α is present. In some embodiments, Z₁ and Z₂ are N.In some embodiments, β is present. In some embodiments, χ and δ areabsent. In certain embodiments, a is present; Z₁ and Z₂ are N; X is N; βis present; and χ and δ are absent.

In some embodiments, c is present. In some embodiments, 4 is present. Insome embodiments, ε and ϕ are each present. In some embodiments, ε and ϕare each absent. In some embodiments, n is 0 or 1. In some embodiments,n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 2.In some embodiments, n is 1. In some embodiments, each of Y₁, Y₂, Y₃,and Y₄, are independently —CR⁴— or N. In some embodiments, each of Y₁,Y₂, Y₃, and each occurrence of Y₄ are independently C(R⁵)₂, NR⁶, O, orSO₂. In some embodiments, ε and ϕ are each present; n=1; and each of Y₁,Y₂, Y₃, and Y₄, are independently —CR⁴— or N. In certain embodiments, εand ϕ are each absent; n is 0, 1 or 2; and each of Y₁, Y₂, Y₃, and eachoccurrence of Y₄ are independently C(R⁵)₂, NR⁶, O, or SO₂.

In some embodiments, α, β, ε, and ϕ are present. In some embodiments, χand δ are absent. In some embodiments, Z₁ is N. In some embodiments, Z₂is N. In certain embodiments, α, β, ε, and ϕ are present; χ and δ areabsent; Z₁ is N; Z₂ is N; and X is N.

In some embodiments, A has the structure:

-   -   wherein:        -   Y₁, Y₂, Y₃ and Y₄ are each independently CR⁴ or N; and        -   each R⁴ is independently H, halogen, C₁-C₁₀ alkyl, C₁-C₁₀            cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH, —C(O)O(C₁-C₁₀ alkyl),            —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂,            —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄ alkyl)₂,            —SO₂NH(C₁-C₁₀ alkyl), —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or C₁-C₁₀            haloalkyl.

In some embodiments, Y₁, Y₂, Y₃ and Y₄ are CR⁴. In some embodiments, Y₁,Y₂, Y₃ are CR⁴ and Y₄ is N. In some embodiments, Y₁, Y₂, Y₄ are CR⁴ andY₃ is N. In some embodiments, Y₁, Y₃, Y₄ are CR⁴ and Y₂ is N. In someembodiments, Y₂, Y₃, Y₄ are CR⁴ and Y₁ is N.

In some embodiments, R³ is H, halogen, C₁-C₁₀ alkyl, C₁-C₁₀ cycloalkyl,—O(C₁-C₁₀ alkyl), —C(O)OH, —C(O)O(C₁-C₁₀ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄alkyl), —C(O)N(C₁-C₄ alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄alkyl)₂, —SO₂NH(C₁-C₁₀ alkyl), —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF₃. Insome embodiments, R³ is H, halogen, C₁-C₆ alkyl, C₁-C₆ cycloalkyl,—O(C₁-C₆ alkyl), —C(O)OH, —C(O)O(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄alkyl), —C(O)N(C₁-C₄ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₄alkyl)₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —CN, or —CF₃.

In some embodiments, each R⁴ is independently H, halogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ cycloalkyl, —O(C₁-C₆ alkyl), —C(O)OH,—C(O)O(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄ alkyl)₂, —SO₂NH(C₁-C₆alkyl), —SO₂N(C₁-C₆ alkyl)₂, or —CN. In some embodiments, each R⁴ isindependently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆cycloalkyl, —O(C₁-C₆ alkyl), —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, or —CN. In some embodiments,each R⁴ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or—CN. In some embodiments, each R⁴ is independently H, halogen, C₁-C₄alkyl, C₃-C₆ cycloalkyl, —O(C₁-C₄ alkyl), —CN, —CF₃, —C(O)OH, —C(O)NH₂,—C(O)N(CH₃)₂, —C(O)NHCH₃, or —NHC(O)N(CH₃)₂. In some embodiments, eachR₄ is independently H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —O(C₁-C₄alkyl), —CN, —CF₃, —C(O)OH, —C(O)NH₂, —C(O)N(CH₃)₂, —C(O)NHCH₃, or—NHC(O)N(CH₃)₂. In some embodiments, each R⁴ is independently H,halogen, methyl, methoxy, —CN, —CF₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, or—C(O)Me. In some embodiments, each R⁴ is independently H, F, methyl,methoxy, —CN, —CF₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, or —C(O)Me. In someembodiments, each R⁴ is independently H, F, methyl, methoxy, —CN, or—CF₃. In some embodiments, each R⁴ is independently H or —CN.

In some embodiments, each R⁵ is independently H or C₁-C₆ alkyl. In someembodiments, R⁵ is H.

In some embodiments, each R⁶ is independently H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, —(C₁-C₆ alkylene)CF₃, —(C₁-C₆ alkylene)OCH₃, —(C₁-C₆alkylene)-halogen, —SO₂—C₁-C₆ alkyl, —SO₂(C₁-C₆ alkylene)-CF₃,—SO₂(C₁-C₆ alkylene)OCH₃, —SO₂(C₁-C₆ alkylene)-halogen, —C(O)(C₁-C₆alkyl), —C(O)(C₁-C₆ alkylene)CF₃, —C(O)(C₁-C₆ alkylene)OCH₃, —C(O)(C₁-C₆alkylene)-halogen, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —(C₁-C₆alkylene)C(O)OH, —C(O)NH₂, or oxetane. In some embodiments, each R⁶ isindependently C₁-C₆ alkyl, C₃-C₆, cycloalkyl, —(C₁-C₆ alkylene)CF₃,—(C₁-C₆ alkylene)OCH₃, —(C₁-C₆ alkylene)-halogen, —SO₂—C₁-C₆ alkyl,—SO₂(C₁-C₆ alkylene)-CF₃, —SO₂(C₁-C₆ alkylene)OCH₃, —SO₂(C₁-C₆alkylene)-halogen, —C(O)(C₁-C₆ alkyl), —C(O(C₁-C₆ alkylene)CF₃,—C(O)(C₁-C₆ alkylene)OCH₃, —C(O)(C₁-C₆ alkylene)-halogen, —C(O))NH(C₁-C₆alkyl), —C(O)NH(C₁-C₆ alkyl)₂, —(C₁-C₆ alkylene)C(O)OH, —C(O)NH₂, oroxetane. In some embodiments, each R⁶ is independently —C(O)(C₁-C₆alkyl). In some embodiments, each R⁶ is independently H, C₁-C₄ alkyl,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, t-Bu, —CH₂OCH₃, —CH₂CF₃, —CH₂Cl,—CH₂F, —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —CH₂CH₂Cl, —CH₂CH₂F,

SO₂CH₂, —SO₂CH₂CH₃, —SO₂CH₂CH₂CH₃, —SO₂CH(CH₃)₂, —SO₂CH₂CH(CH₃)₂,—SO₂(t-Bu), —SO₂CH₂OCH₃, —SO₂CH₂CF₃, —SO₂CH₂Cl, —SO₂CH₂F,—SO₂CH₂CH₂OCH₃, —SO₂CH₂CH₂CF₃, —SO₂CH₂CH₂Cl, —SO₂CH₂CH₂F,

C(O)CH₃, C(O)CH₂CH₃, —C(O)CH₂CH₂CH₃, —C(O)CH(CH₃)₂, —C(O)CH₂CH(CH₃)₂,—C(O)t-Bu, —C(O)CH₂OCH₃, —C(O)CH₂CF₃, —C(O)CH₂Cl, —C(O)CH₂F,—C(O)CH₂CH₂OCH₃, —C(O)CH₂CH₂CF₃, —C(O)CH₂CH₂Cl, —C(O)CH₂CH₂F,

In some embodiments, each R⁶ is independently —C(O)(C₁-C₆ alkyl). Insome embodiments, each R⁶ is independently H, C₁-C₄ alkyl, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, t-Bu, —CH₂OCH₃, —CH₂CF₃, —CH₂Cl, —CH₂F,—CH₂CH₂OCH₃, —CH₂CH₂CF₃, —CH₂CH₂Cl, —CH₂CH₂F, or

In other embodiments, each R⁶ is independently —SO₂CH—₃, —SO₂CH₂CH₃,—SO₂CH₂CH₂CH₃, —SO₂CH(CH₃)₂, —SO₂CH₂CH(CH₃)₂, —SO₂(t-Bu), —SO₂CH₂OCH₃,—SO₂CH₂CF₃, —SO₂CH₂Cl, —SO₂CH₂F, —SO₂CH₂CH₂OCH₃, —SO₂CH₂CH₂CF₃,—SO₂CH₂CH₂Cl, —SO₂CH—₂CH₂F, or

In certain embodiments, each R⁶ is independently C(O)CH₃, C(O)CH₂CH₃,—C(O)CH₂CH₂CH₃, —C(O)CH(CH₃)₂, —C(O)CH₂CH(CH₃)₂, —C(O)t-Bu,—C(O)CH₂OCH₃, —C(O)CH₂CF₃, —C(O)CH₂Cl, —C(O)CH₂F, —C(O)C₂CH₂OCH₃,—C(O)CH₂CH₂CF₃, —C(O)CH₂CH₂Cl, —C(O)CH₂CH₂F

In some embodiments, A has the structure:

In some embodiments, A has the structure:

In some embodiments, A has the structure:

In some embodiments, A has the structure

In some embodiments, A has the structure:

In some embodiments, the heterocyclic compounds of Formula (I) areprovided in Table 1.

TABLE 1 Compound No. Name Structure  13-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

 2 3-(4-(3-fluoro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

 3 1,1-dimethyl-3-(3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-6- yl)urea

 4 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-7- carboxylic acid

 5 N,N-dimethyl-3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-7- carboxamide

 6 (6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

 7 N-methyl-3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-7- carboxamide

 8 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-7- carboxamide

 9 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

10 (7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

11 (7-(trifluoromethyl)-[1,2,4]triazolo[4,3- a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

12 (6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

13 (6-(trifluoromethyl)-[1,2,4]triazolo[4,3- a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

14 (6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

15 (6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

16 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid

17 N,N-dimethyl-3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carboxamide

18 N-methyl-3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carboxamide

19 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carboxamide

20 (6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

21 1-(3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethan-1-one

22 (7-(methylsulfonyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

23 (6-(methylsulfonyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

24 1-(3-(4-(2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-7,8-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-6(5H)-yl)ethan-1-one

25 (5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

26 (5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- c]pyrimidin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

27 (5,6-dihydro-8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

28 (7,8-dihydro-5H-[1,2,4]triazolo[4,3- c][1,3]oxazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

29 (7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

30 (6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

31 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(3-chloro-2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

32 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

33 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

34 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

35 (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(6-methoxy-[1,2,4]triazolo[4,3- a]pyridin-3-yl)methanone

36 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

37 3-(4-(2-fluoro-6- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

38 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

39 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

40 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-3-fluorophenyl)piperidin-1- yl)methanone

41 3-(4-(3-chloro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

42 3-(4-(5-chloro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

43 3-(4-(4-fluoro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

44 3-(4-(3,5-difluoro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

45 3-(4-(5-fluoro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6- carbonitrile

46 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

47 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1- yl)methanone

48 (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl)piperidin-1- yl)methanone

Preparation of Compounds

The compounds used in the chemical reactions described herein are madeaccording to organic synthesis techniques known to those skilled in thisart, starting from commercially available chemicals and/or fromcompounds described in the chemical literature. “Commercially availablechemicals” are obtained from standard commercial sources including AcrosOrganics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., includingSigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK),Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Alternatively, specific and analogous reactants can be identifiedthrough the indices of known chemicals and reactions prepared by theChemical Abstract Service of the American Chemical Society, which areavailable in most public and university libraries, as well as throughon-line databases (contact the American Chemical Society, Washington,D.C. for more details). Chemicals that are known but not commerciallyavailable in catalogs are optionally prepared by custom chemicalsynthesis houses, where many of the standard chemical supply houses(e.g., those listed above) provide custom synthesis services. Areference for the preparation and selection of pharmaceutical salts ofthe heterocyclic RBP4 inhibitory compound described herein is P. H.Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, VerlagHelvetica Chimica Acta, Zurich, 2002.

Retinol Binding Protein 4 (RBP4)

Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood,is secreted from adipocytes and liver. Serum RBP4 levels correlatehighly with insulin resistance, other metabolic syndrome factors, andcardiovascular disease. In some instances, elevated serum RBP4 causesinsulin resistance and impaired glucose tolerance. In some instances,lowering of serum RBP4 improves insulin action and glucose tolerance. Insome embodiments, the compounds described herein lower serum or plasmaRBP4 and thus improve insulin action and glucose tolerance.

In some embodiments, 48 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 30% from baseline. Insome embodiments, 48 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 40% from baseline. In someembodiments, 48 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 50% from baseline. Inother embodiments, 48 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 65% from baseline. Incertain embodiments, 48 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 80% from baseline. Insome embodiments, 48 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 36 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 30% from baseline. Insome embodiments, 36 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 40% from baseline. In someembodiments, 36 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 50% from baseline. Inother embodiments, 36 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 65% from baseline. Incertain embodiments, 36 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 80% from baseline. Insome embodiments, 36 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 30% from baseline. Insome embodiments, 24 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 40% from baseline. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 50% from baseline. Inother embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 65% from baseline. Incertain embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 80% from baseline. Insome embodiments, 24 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 12 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 30% from baseline. Insome embodiments, 12 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 40% from baseline. In someembodiments, 12 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 50% from baseline. Inother embodiments, 12 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 65% from baseline. Incertain embodiments, 12 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 80% from baseline. Insome embodiments, 12 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 6 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 20% from baseline. Insome embodiments, 6 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 25% from baseline. In someembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 30% from baseline. In someembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 40% from baseline. In someembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 50% from baseline. Inother embodiments, 6 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 65% from baseline. Incertain embodiments, 6 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 80% from baseline. Insome embodiments, 6 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 48 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In otherembodiments, 48 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 48 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In certainembodiments, 48 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In someembodiments, 48 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

In some embodiments, 36 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In otherembodiments, 36 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 36 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In certainembodiments, 36 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In someembodiments, 36 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

In some embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In otherembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In certainembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

In some embodiments, 12 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In otherembodiments, 12 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 12 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In certainembodiments, 12 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In someembodiments, 12 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

In some embodiments, 6 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In otherembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In certainembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In someembodiments, 6 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

Methods of Treatment

In some embodiments, a compound disclosed herein is used to treat orameliorate a disease associated with altered RBP4 pathways whenadministered to a subject in need thereof. In some cases, a compounddisclosed herein is used to treat or ameliorate the effects of a diseaseassociated with altered RBP4 pathway when administered to a subject inneed thereof. Exemplary diseases associated with altered RBP4 includemetabolic diseases. In some instances, a compound disclosed herein isused to treat or ameliorate a metabolic disease when administered to asubject in need thereof. Exemplary metabolic diseases include NASH,NAFLD, type II diabetes, diabetic retinopathy, obesity, fibrosis,cirrhosis, or liver cancer. In one embodiment, the fatty liver diseaseis selected from the group consisting of non-alcoholic fatty acid liverdisease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liverdisease resulting from hepatitis, fatty liver disease resulting fromobesity, fatty liver disease resulting from diabetes, fatty liverdisease resulting from insulin resistance, fatty liver disease resultingfrom hypertriglyceridemia, Abetalipoproteinemia, glycogen storagediseases, Weber-Christian disease, Wolmans disease, acute fatty liver ofpregnancy, and lipodystrophy. Heterocyclic RBP4 inhibitory compoundsdisclosed herein are in some embodiments used to modulate variousprotein levels which result in improved disease outcomes. For example,proteins variously include cytokines or other protein. In someembodiments, a compound described herein provides for a decrease in aninflammatory cytokine. In some embodiments, a heterocyclic RBP4inhibitory compound described herein provides for a decrease in IL6,MCP, TNF-α, or any combination thereof. In some embodiments, theheterocyclic RBP4 inhibitory compounds described herein provide adecrease in IL6. In some embodiments, the heterocyclic RBP4 inhibitorycompounds described herein provide a decrease in MCP. In someembodiments, the heterocyclic RBP4 inhibitory compounds described hereinprovide a decrease in TNF-α.

Non-Alcoholic Steatohepatitis (NASH)

Non-alcoholic steatohepatitis or NASH is a common liver disease, whichresembles alcoholic liver disease, but occurs in people who drink littleor no alcohol. The major feature in NASH is fat in the liver, along withinflammation and damage. In some instances, NASH progresses intoadvanced NASH, which is characterized, inter cilia, by hepatic fibrosis.In certain instances, NASH progresses to cirrhosis, in which the liveris damaged, scarred, and is no longer able to work properly. In someinstances, a person with cirrhosis experiences fluid retention, musclewasting, bleeding from the intestines, and/or liver failure. In someinstances. NASH is associated with an increased risk of cardiovascularmortality and type II diabetes mellitus. Cirrhosis due to NASH increasesthe risk of hepatocellular carcinoma.

NASH is usually first suspected in a person who is found to haveelevations in liver tests that are included in routine blood testpanels, such as alanine aminotransferase (ALT) or aspartateaminotransferase (AST). When further evaluation shows no apparent reasonfor liver disease (such as medications, viral hepatitis, or excessiveuse of alcohol) and when X-rays or imaging studies of the liver showfat, NASH is suspected. NASH is diagnosed and separated from NAFLD by aliver biopsy. For a liver biopsy, a needle is inserted through the skinto remove a small piece of the liver. NASH is diagnosed when examinationof the tissue with a microscope shows fat along with inflammation anddamage to liver cells. A biopsy can provide information about scartissue has development in the liver.

Some embodiments provided herein describe the use of the heterocyclicRBP4 inhibitory compounds described herein for treating NASH in asubject in need thereof. In some embodiments, the heterocyclic RBP4inhibitory compounds inhibit NASH. In specific embodiments, theheterocyclic RBP4 inhibitory compounds arrest the development of NASH orits clinical symptoms. In other embodiments, the heterocyclic RBP4inhibitory compounds reduce the development of NASH or its clinicalsymptoms. In certain embodiments, the heterocyclic RBP4 inhibitorycompounds relieve the subject of NASH. In specific embodiments, theheterocyclic RBP4 inhibitory compounds cause regression, reversal oramelioration of NASH. In certain specific embodiments, the heterocyclicRBP4 inhibitory compounds reduce the number, frequency, duration, orseverity of NASH clinical symptoms. In some embodiments, an RBP4inhibitory compound described herein provide a reduction in NASHfibrosis scores. In some embodiments, an RBP4 inhibitory compounddescribed herein provide a decrease in the number of bridging fibrosis.In some embodiments, the heterocyclic RBP4 inhibitory compounds are usedprophylactically. In specific embodiments, the heterocyclic RBP4inhibitory compounds are used to prevent or reduce the risk ofdeveloping NASH. In certain specific embodiments, the heterocyclic RBP4inhibitory compounds cause the clinical symptoms of NASH not to developin a subject who may be predisposed to NASH but who does not yetexperience or display symptoms of NASH.

Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a disorder affecting asmany as 1 in 3-5 adults and 1 in 10 children in the United States, andrefers to conditions where there is an accumulation of excess fat in theliver of people who drink little or no alcohol. The most common form ofNAFLD is a non-serious condition called hepatic steatosis (fatty liver),in which fat accumulates in the liver cells. NAFLD most often presentsitself in individuals with a constellation of risk factors called themetabolic syndrome, which is characterized by elevated fasting plasmaglucose (FPG) with or without intolerance to post-prandial glucose,being overweight or obese, high blood lipids such as cholesterol andtriglycerides (TGs) and low high-density lipoprotein cholesterol (HDL-C)levels, and high blood pressure; but not all patients have all themanifestations of the metabolic syndrome. Obesity is thought to be themost common cause of NAFLD; and some experts estimate that abouttwo-thirds of obese adults and one-half of obese children may have fattyliver. The majority of individuals with NAFLD have no symptoms and anormal physical examination (although the liver may be slightlyenlarged); children may exhibit symptoms such as abdominal pain andfatigue, and may show patchy dark skin discoloration (acanthosisnigricans). The diagnosis of NAFLD is usually first suspected in anoverweight or obese person who is found to have mild elevations in theirliver blood tests during routine testing, though NAFLD can be presentwith normal liver blood tests, or incidentally detected on imaginginvestigations such as abdominal ultrasound or CT scan. It is confirmedby imaging studies, most commonly a liver ultrasound or magneticresonance imaging (MRI), and exclusion of other causes.

Some embodiments provided herein describe the use of the heterocyclicRBP4 inhibitory compounds described herein for treating NAFLD in asubject in need thereof. In some embodiments, the heterocyclic RBP4inhibitory compounds inhibit NAFLD. In specific embodiments, theheterocyclic RBP4 inhibitory compounds arrest the development of NAFLDor its clinical symptoms. In other embodiments, the heterocyclic RBP4inhibitory compounds reduce the development of NAFLD or its clinicalsymptoms. In certain embodiments, the heterocyclic RBP4 inhibitorycompounds relieve the subject of NAFLD. In specific embodiments, theheterocyclic RBP4 inhibitory compounds cause regression, reversal oramelioration of NAFLD. In certain specific embodiments, the heterocyclicRBP4 inhibitory compounds reduce the number, frequency, duration, orseverity of NAFLD clinical symptoms.

In some embodiments, the heterocyclic RBP4 inhibitory compounds are usedprophylactically. In specific embodiments, the heterocyclic RBP4inhibitory compounds are used to prevent or reduce the risk ofdeveloping NAFLD. In certain specific embodiments, the heterocyclic RBP4inhibitory compounds cause the clinical symptoms of NAFLD not to developin a subject who may be predisposed to NAFLD but who does not yetexperience or display symptoms of NAFLD.

Type II Diabetes

Type II diabetes is a metabolic disorder characterized by hyperglycemiaand abnormities in the glucose-protein- and lipid-metabolism. Type IIdiabetes is caused by insulin resistance which is not adequatelycompensated due to an insufficient β-cell secretory capacity. In recentyears, type II diabetes and its chronic complications have become amajor threat to human health. Long-term hyperglycemia associated withtype II diabetes results in the damage of many tissues and organs, whichin turn leads to a variety of diabetic chronic complications, such ascoronary heart disease, atherosclerosis, cerebrovascular disease andother diabetic macrovascular diseases, diabetic nephropathy, diabeticretinopathy and other diabetic microangiopathy, diabetic neuropathy,diabetic foot, diabetic maculopathy, diabetic cataract, diabeticglaucoma, refractive changes, iris and ciliary body diseases.

Some embodiments provided herein describe the use of the heterocyclicRBP4 inhibitory compounds described herein for treating type IIdiabetes, including its chronic complications, in a subject in needthereof. In some embodiments, the heterocyclic RBP4 inhibitory compoundsinhibit type II diabetes, including its chronic complications. Inspecific embodiments, the heterocyclic RBP4 inhibitory compounds arrestthe development of type II diabetes, its chronic complications, or itsclinical symptoms. In other embodiments, the heterocyclic RBP4inhibitory compounds reduce the development of type II diabetes, itschronic complications, or its clinical symptoms. In certain embodiments,the heterocyclic RBP4 inhibitory compounds relieve the subject of typeII diabetes, its chronic complications, or its clinical symptoms. Inspecific embodiments, the heterocyclic RBP4 inhibitory compounds causeregression, reversal, or amelioration of type II diabetes, its chroniccomplications, or its clinical symptoms. In certain specificembodiments, the heterocyclic RBP4 inhibitory compounds reduce thenumber, frequency, duration, or severity of type II diabetes, itschronic complications, or its clinical symptoms.

In some embodiments, the heterocyclic RBP4 inhibitory compounds are usedprophylactically. In specific embodiments, the heterocyclic RBP4inhibitory compounds are used to prevent or reduce the risk of type IIdiabetes, its chronic complications, or its clinical symptoms. Incertain specific embodiments, the heterocyclic RBP4 inhibitory compoundscause the clinical symptoms of type II diabetes not to develop in asubject who may be predisposed to type II diabetes but who does not yetexperience or display symptoms of type II diabetes. In some embodiments,the subject is genetically, environmentally, dietarily or sociallypredisposed to type II diabetes.

Obesity

Obesity and disorders associated with obesity such as diabetes are amajor global health concern. Obesity, which is generally associated withan abnormal accumulation of fat cells, develops when energy intakeexceeds energy expenditure.

Obesity is associated with an increased risk of diabetes. Most obesepeople are insulin resistant and have to adapt by increasing insulinsecretion. In some instances, type II diabetes mellitus manifests inindividuals who lose the ability to produce sufficient quantities ofinsulin to maintain normoglycemia in the face of insulin resistance.

Obesity is a state of chronic, low-grade inflammation, and macrophagesare thought to play an important role in maintaining this state inadipose tissue. Many molecules secreted by adipose tissue promoteadipose tissue inflammation. Emerging evidence suggests a possible rolefor proinflammatory pathways in RBP4-induced insulin resistance. RBP4expression in adipose tissue and serum RBP4 levels strongly correlatewith subclinical inflammation, including serum levels and adipose tissueexpression of proinflammatory cytokines.

Some embodiments provided herein describe the use of the heterocyclicRBP4 inhibitory compounds described herein for treating obesity in asubject in need thereof. In specific embodiments, the heterocyclic RBP4inhibitory compounds arrest the development of obesity or its clinicalsymptoms. In other embodiments, the heterocyclic RBP4 inhibitorycompounds reduce the development of obesity or its clinical symptoms. Incertain embodiments, the heterocyclic RBP4 inhibitory compounds relievethe subject of obesity. In specific embodiments, the heterocyclic RBP4inhibitory compounds cause regression, reversal or amelioration ofobesity. In certain specific embodiments, the heterocyclic RBP4inhibitory compounds reduce the number, frequency, duration, or severityof obesity clinical symptoms.

In some embodiments, the heterocyclic RBP4 inhibitory compounds are usedprophylactically. In specific embodiments, the heterocyclic RBP4inhibitory compounds are used to prevent or reduce the risk ofdeveloping obesity. In certain specific embodiments, the heterocyclicRBP4 inhibitory compounds cause the clinical symptoms of obesity not todevelop in a subject who may be predisposed to obesity but who does notyet experience or display symptoms of obesity. In some embodiments, aheterocyclic RBP4 inhibitory compound improves plasma insulin levels. Insome embodiments, a heterocyclic RBP4 inhibitory compound improvesglucose tolerance levels.

Pharmaceutical Compositions

In certain embodiments, the heterocyclic RBP4 inhibitory compound asdescribed herein is administered as a pure chemical. In otherembodiments, the heterocyclic RBP4 inhibitory compound described hereinis combined with a pharmaceutically suitable or acceptable carrier (alsoreferred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Provided herein is a pharmaceutical composition comprising at least oneheterocyclic RBP4 inhibitory compound, or a stereoisomer,pharmaceutically acceptable salt, or N-oxide thereof, together with oneor more pharmaceutically acceptable carriers. The carrier(s) (orexcipient(s)) is acceptable or suitable if the carrier is compatiblewith the other ingredients of the composition and not deleterious to therecipient (i.e., the subject or patient) of the composition.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient. In one embodiment, thepharmaceutical compositions are provided in a dosage form for oraladministration, which comprise a compound provided herein, and one ormore pharmaceutically acceptable excipients or carriers.

In certain embodiments, the heterocyclic RBP4 inhibitory compound asdescribed by Formula (I) is substantially pure, in that it contains lessthan about 5%, or less than about 1%, or less than about 0.1%, of otherorganic small molecules, such as unreacted intermediates or synthesisby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

In some embodiments, the pharmaceutical compositions provided herein areformulated for oral administration in tablet, capsule, powder, or liquidform. In some embodiments, a tablet comprises a solid carrier or anadjuvant. Liquid pharmaceutical compositions generally comprise a liquidcarrier such as water, petroleum, animal or vegetable oils, mineral oil,or synthetic oil. In some embodiments, physiological saline solution,dextrose or other saccharide solution, or glycols are optionallyincluded. In some embodiments, a capsule comprises a solid carrier suchas gelatin.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers. Where pharmaceutical compositions are formulated forintravenous, cutaneous or subcutaneous injection, the active ingredientis in the form of a parenterally acceptable aqueous solution, which ispyrogen-free and has a suitable pH, isotonicity, and stability. Those ofrelevant skill in the art are well able to prepare suitable solutionsusing, for example, isotonic vehicles, such as Sodium Chlorideinjection, Ringer's injection, or Lactated Ringer's injection. In someembodiments, preservatives, stabilizers, buffers, antioxidants, and/orother additives are included.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

Methods of Dosing and Treatment Regimens

The dose of the composition comprising at least one heterocyclic RBP4inhibitory compound as described herein differ, depending upon thepatient's condition, that is, stage of the disease, general healthstatus, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome), or a lessening of symptom severity. Optimal doses aregenerally determined using experimental models and/or clinical trials.The optimal dose depends upon the body mass, weight, or blood volume ofthe patient.

In one embodiment, the compounds described herein, or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom administration of any one of the compounds disclosed. Methods fortreating any of the diseases or conditions described herein in a mammalin need of such treatment, involves administration of pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, in which the mammal previously experienced at least onesymptom of the disease being treated and is currently in remission, apharmaceutical composition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day. In general, however, doses employed foradult human treatment are typically in the range of 0.01 mg to 5000 mgper day. In one aspect, doses employed for adult human treatment arefrom about 1 mg to about 1000 mg per day. In one embodiment, the desireddose is conveniently presented in a single dose or in divided dosesadministered simultaneously or at appropriate intervals, for example astwo, three, four or more sub-doses per day.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 15 mg, about 20 mg, about 25 mg, about 30 mg,about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg,about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg,about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg,about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg,about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 240 mg,about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg,about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, orabout 500 mg. In some embodiments, a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of up to about 15 mg, up to about 20mg, up to about 25 mg, up to about 30 mg, up to about 35 mg, up to about40 mg, up to about 45 mg, up to about 50 mg, up to about 55 mg, up toabout 60 mg, up to about 65 mg, up to about 70 mg, up to about 75 mg, upto about 80 mg, up to about 85 mg, up to about 90 mg, up to about 95 mg,up to about 100 mg, up to about 105 mg, up to about 110 mg, up to about115 mg, up to about 120 mg, up to about 125 mg, up to about 130 mg, upto about 135 mg, up to about 140 mg, up to about 145 mg, up to about 150mg, up to about 155 mg, up to about 160 mg, up to about 165 mg, up toabout 170 mg, up to about 175 mg, up to about 180 mg, up to about 185mg, up to about 190 mg, up to about 195 mg, up to about 200 mg, up toabout 225 mg, up to about 240 mg, up to about 250 mg, up to about 275mg, up to about 300 mg, up to about 325 mg, up to about 350 mg, up toabout 375 mg, up to about 400 mg, up to about 425 mg, up to about 450mg, up to about 475 mg, or up to about 500 mg. In some embodiments, acompound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of at least 15 mg,at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg,at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg,at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, atleast 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, atleast 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, atleast 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, atleast 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, atleast 240 mg, at least 250 mg, at least 275 mg, at least 300 mg, atleast 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, atleast 425 mg, at least 450 mg, at least 475 mg, or at least 500 mg.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg,about 150 mg, about 200 mg, or about 400 mg. In some embodiments, acompound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of about 50 mg,about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In someembodiments, a compound of Formula (I), a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, orisomer thereof is administered to a subject or patient in an amount ofup to 25 mg, up to 50 mg, up to 75 mg, up to 100 mg, up to 150 mg, up to200 mg, or up to 400 mg. In some embodiments, a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of at least 25 mg, at least 50 mg, atleast 75 mg, at least 100 mg, at least 150 mg, at least 200 mg, or atleast 400 mg. In some embodiments, a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of up to 25 mg, up to 50 mg, up to 75mg, up to 100 mg, up to 150 mg, up to 200 mg, up to 400 mg, up to 600mg, up to 800 mg, or up to 1000 mg.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 25 mg per day, about 50 mg per day, about 75 mgper day, about 100 mg per day, about 150 mg per day, about 200 mg perday, or about 400 mg per day. In some embodiments, a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of about 50 mg per day, about 100 mgper day, about 150 mg per day, about 200 mg per day, or about 400 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 25 mg per day, up to 50 mg per day, up to 75 mgper day, up to 100 mg per day, up to 150 mg per day, up to 200 mg perday, or up to 400 mg per day. In some embodiments, a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of at least 25 mg per day, at least 50mg per day, at least 75 mg per day, at least 100 mg per day, at least150 mg per day, at least 200 mg per day, or at least 400 mg per day. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 25 mg per day, up to 50 mg per day, up to 75 mgper day, up to 100 mg per day, up to 150 mg per day, up to 200 mg perday, up to 400 mg per day, up to 600 mg per day, up to 800 mg per day,or up to 1000 mg per day.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 400 mg. In some embodiments, a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of up to 200 mg. In some embodiments,a compound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of up to 150 mg. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 100 mg. In some embodiments, a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of up to 75 mg. In some embodiments, acompound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of up to 50 mg. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 25 mg.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 400 mg per day. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of up to 200 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 150 mg per day. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of up to 100 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 75 mg per day. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of up to 50 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of up to 25 mg per day.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 400 mg. In some embodiments, a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of about 200 mg. In some embodiments,a compound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of about 150 mg. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 100 mg. In some embodiments, a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of about 75 mg. In some embodiments, acompound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of about 50 mg. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 25 mg.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 400 mg per day. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of about 200 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 150 mg per day. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of about 100 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 75 mg per day. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of about 50 mg perday. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of about 25 mg per day.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 400 mg. In some embodiments, a compoundof Formula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of at least about 200mg. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 150 mg. In some embodiments, a compoundof Formula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of at least about 100mg. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 75 mg. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered to a subject or patient in an amount of at least about 50mg. In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 25 mg.

In some embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 400 mg per day. In some embodiments, acompound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of at least about200 mg per day. In some embodiments, a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of at least about 150 mg per day. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 100 mg per day. In some embodiments, acompound of Formula (I), a pharmaceutically acceptable salt, solvate,polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereofis administered to a subject or patient in an amount of at least about75 mg per day. In some embodiments, a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administered toa subject or patient in an amount of at least about 50 mg per day. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered to a subject or patientin an amount of at least about 25 mg per day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg/kg per body weight. In some embodiments,the daily dosage or the amount of active in the dosage form are lower orhigher than the ranges indicated herein, based on a number of variablesin regard to an individual treatment regime. In various embodiments, thedaily and unit dosages are altered depending on a number of variablesincluding, but not limited to, the activity of the compound used, thedisease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD50 and the ED50. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD50 and ED50. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED50 with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal. In some embodiments, a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administeredorally or parenterally to the subject in need thereof. Parenteraladministration, as used herein, include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular, intrasynovial, intravesical,and subcutaneous administration. In some embodiments, a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof isadministered orally or intravenously to a subject in need thereof. Insome embodiments, a compound of Formula (I), a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide,stereoisomer, or isomer thereof is administered orally to a subject inneed thereof. In some embodiments, a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is administeredintravenously to a subject in need thereof.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day, e.g., two, three, four or more timesdaily. In some embodiments, the heterocyclic RBP4 inhibitory compoundsdescribed herein are administered daily, every other day, every otherday 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly,bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times aweek, once a month, twice a month, 3 times a month, once every 2 months,once every 3 months, once every 4 months, once every 5 months, or onceevery 6 months. In some embodiments, the heterocyclic RBP4 inhibitorycompounds described herein, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, orisomer thereof, are administered daily.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (e.g., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%. In further or alternative embodiments, the methodcomprises a drug holiday, wherein the administration of the compound istemporarily suspended or the dose of the compound being administered istemporarily reduced; at the end of the drug holiday, dosing of thecompound is resumed. In one embodiment, the length of the drug holidayvaries from 2 days to 7 days. In one embodiment, the length of the drugholiday is 7 days. In one embodiment, the length of the drug holiday is14 days. In one embodiment, the length of the drug holiday is 28 days.

Provided herein are methods for the treatment of obesity, diabetes,non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis withheterocyclic derivative compounds and pharmaceutical compositionsthereof.

Some embodiments provided herein describe methods of treating ametabolic disease or disorder in a subject in need thereof, the methodcomprising administering to the subject a composition comprising atherapeutically effective amount of a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof:

wherein:

-   -   each R¹ is independently halogen, haloalkyl, or alkyl,    -   R² is —H, —OH, or halogen;    -   p is 0, 1, 2, 3, 4, or 5;    -   A has the structure:

wherein:

-   -   α, β, χ, and δ are each independently absent or present, and        when present each is a bond;    -   X is N;    -   Z₁ is S, O, or N;    -   Z₂ is S, O, N, or NR³;    -   R³ is H, C₁-C₄ alkyl, or oxetane; and    -   B is a substituted or unsubstituted fused 5-, 6-, or 7-membered        ring structure.

In some embodiments of a compound of Formula (I), when α is present,then Z₁ and Z₂ are N, X is N, β is present, and χ and δ are absent.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), A has the structure

wherein:

-   -   n is 0, 1, or 2;    -   α, β, χ, δ, ε, and ϕ are each independently absent or present,        and when present each is a bond;    -   Z₁ is S, O, or N;    -   Z₂ is S, O, N or NR³,        -   wherein R is H, C₁-C₄ alkyl, or oxetane;    -   X is N;    -   Y₁, Y₂, Y₃ and each occurrence of Y₄ are each independently CR⁴,        C(R⁵)₂, NR⁶, O, N, SO₂, or —(C═O)—, wherein:        -   each R⁴ is independently H, halogen, C₁-C₁₀ alkyl, C₁-C₁₀            cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH, —C(O)O(C₁-C₁₀ alkyl),            —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂,            —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄ alkyl)₂,            —SO₂NH(C₁-C₁₀ alkyl), —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF₃,        -   each R⁵ is independently H or C₁-C₁₀ alkyl; and        -   each R⁶ is independently H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl,            —(C₁-C₁₀ alkyl)CF₃, —(C₁-C₁₀ alkyl)OCH₃, —(C₁-C₁₀            alkyl)-halogen, —SO₂(C₁-C₁₀ alkyl), —SO₂(C₁-C₁₀ alkyl)-CF₃,            —SO₂(C₁-C₁₀ alkyl)OCH₃, —SO₂(C₁-C₁₀ alkyl)-halogen,            —C(O)(C₁-C₁₀ alkyl), —C(O)(C₁-C₁₀ alkyl)CF₃, —C(O)(C₁-C₁₀            alkyl)OCH₃, —C(O)(C₁-C₁₀ alkyl)-halogen, —C(O)NH(C₁-C₁₀            alkyl), —C(O)N(C₁-C₁₀ alkyl)₂, —(C₁-C₁₀ alkyl)C(O)OH,            —C(O)NH₂, or oxetane.

In some embodiments of a compound of Formula (I), when α is present,then Z₁ and Z₂ are N, X is N, β is present, and χ and δ are absent; whenε and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃, and Y₄, areindependently —CR⁴— or N; or when ε and ϕ are each absent, then n=0, 1or 2, each of Y₁, Y₂, Y₃, and each occurrence of Y₄ are independentlyC(R⁵)₂, NR⁶, O, or SO₂.

In some embodiments of a compound of Formula (I), where in α, β, ε, andϕ are present; χ and δ are absent; Z₁ is N; Z₂ is N; and X is N.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I),

-   -   A has the structure:

wherein:

-   -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₄ or N; and        -   each R⁴ is independently H, halogen, C₁-C₁₀, alkyl, C₁-C₁₀            cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH, —C(O)O(C₁-C₁₀ alkyl),            —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂,            —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄ alkyl)₂,            —SO₂NH(C₁-C₁₀ alkyl), —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF₃.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), A has the structure:

-   -   wherein:        -   each R₄ is independently H, halogen, C₁-C₄ alkyl, C₃-C₆            cycloalkyl, —O(C₁-C₄ alkyl), —CN, —CF₃, —C(O)OH, —C(O)NH₂,            —C(O)N(CH₃)₂, —C(O)NHCH₃, or —NHC(O)N(CH₃)₂.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), each R¹ is independentlyF, Br, Cl, C₁₋₆ haloalkyl, or C₁₋₆ alkyl.

In some embodiments of a method of treating a metabolic disease ordisorder comprising a compound of Formula (I), wherein each R¹ isindependently F or CF₃.

One embodiment provides a method of treating a metabolic disease ordisorder in a subject in need thereof, the method comprisingadministering to the subject a composition comprising a therapeuticallyeffective amount of a compound having the structure:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof.

One embodiment provides a method of treating a metabolic disease ordisorder in a subject in need thereof the method comprisingadministering to the subject a composition comprising a therapeuticallyeffective amount of a compound having the structure:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments, the metabolic disease or disorder is obesity, typeII diabetes, diabetic retinopathy, non-alcoholic fatty liver disease(NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, livercancer, or liver cirrhosis.

In some embodiments, the therapeutically effective amount of a compoundof Formula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is about25 mg per day, about 50 mg per day, about 75 mg per day, about 100 mgper day, about 150 mg per day, about 200 mg per day, or about 400 mg perday.

In some embodiments, the therapeutically effective amount of a compoundof Formula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is about50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mgper day, or about 400 mg per day. In some embodiments, thetherapeutically effective amount of a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof is up to 25 mg perday, up to 50 mg per day, up to 75 mg per day, up to 100 mg per day, upto 150 mg per day, up to 200 mg per day, or up to 400 mg per day. Insome embodiments, the therapeutically effective amount of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is up to400 mg per day.

In some embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 50% from baseline. Insome embodiments, 24 hours after administration of a compound of Formula(I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite. N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 65% from baseline. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 80% from baseline. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 85% from baseline.

In some embodiments, 24 hours after administration of a compound ofFormula (I), a pharmaceutically acceptable salt, solvate, polymorph,prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serumor plasma levels of RBP4 are reduced by at least 1 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 2 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 5 mg/dL. In someembodiments, 24 hours after administration of a compound of Formula (I),a pharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite. N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 10 mg/dL. In some, 24hours after administration of a compound of Formula (I), apharmaceutically acceptable salt, solvate, polymorph, prodrug,metabolite, N-oxide, stereoisomer, or isomer thereof, the serum orplasma levels of RBP4 are reduced by at least 15 mg/dL.

In some embodiments, the disease or disorder is obesity. In someembodiments, the disease or disorder is type II diabetes. In someembodiments, the disease or disorder is non-proliferative diabeticretinopathy (NPDR) or proliferative diabetic retinopathy (PDR). In someembodiments, the disease or disorder is a liver disease. In someembodiments, the disease or disorder is non-alcoholic fatty liverdisease (NAFLD). In some embodiments, the disease or disorder isnon-alcoholic steatohepatitis (NASH). In some embodiments, the diseaseor disorder is liver fibrosis. In some embodiments, the disease ordisorder is liver cirrhosis. In some embodiments, the disease ordisorder is liver cancer.

In some embodiments of a method of treating a metabolic disorder, thecompound is administered to the subject orally or intravenously. Incertain embodiments, the compound of Formula (I) is administered orally.In certain embodiments, the compound of Formula (I) is administeredintravenously. In some embodiments, the administration is to treat anexisting disease or disorder. In some embodiments, the administration isprovided as prophylaxis.

EXAMPLES Example 1: Compound 1 Single Dose Rat PK Study

A pharmacokinetic study of Compound 1 following a single intravenous ororal dose administration to male Sprague Dawley rats was conducted, theresults of which are found in Table 2 and FIGS. 1-6.

TABLE 2 T_(max) C_(max) t_(1/2) AUC_(LAST) AUC_(inf) Cl V_(ss)MRT_(last) F Rat # (hr)^(a) (ng/ml) (hr) (hr · ng/ml) (hr · ng/ml)(ml/hr/kg) (ml/kg) (hr) (%) iv, 2 mg/kg 1 0.083 2365 6.2 2768 2781 7191932 2.5 NA 2 0.083 1595 8.6 2429 2465 812 2756 2.7 NA 3 0.083 2380 6.12711 2722 735 1922 2.4 NA Mean 0.083 2113 7.0 2636 2656 755 2203 2.6 A4SD 0.000 449 1.4 181 168 49 479 0.2 po, 5 mg/kg 4 1.00 227 6.4 1845 1858NC NC 7.9 28.0 5 1.00 548 5.4 2953 2961 NC NC 5.1 44.6 6 1.00 455 6.13646 3663 NC NC 8.0 55.2 Mean 1.00 410 6.0 2815 2827 NC NC 7.0 42.6 SD0.00 165 0.5 908 910 1.6 13.7 ^(a)For the iv group, the first plasmacollection time is listed as the T_(max); NA = not applicable; NC = notcalculated.

Example 2: Compound 1 Single Dose Mouse PK Study

A pharmacokinetic study of Compound 1 following a single intravenous ororal dose administration to male CD-1 mice was conducted, the results ofwhich are found in Table 3 and FIGS. 7-12.

TABLE 3 Dose T_(max) C_(max) t_(1/2) AUC_(LAST) AUC_(inf) Cl V_(ss)MRT_(last) MRT_(inf) F Route (mg/kg) (hr) (ng/ml)^(a) (hr) (hr · ng/ml)(hr · ng/ml) (ml/hr/kg) (ml/kg) (hr) (hr) (%) iv 2 0.083^(b) 2973 5.712197 12232 163.5 1123 6.7 6.9 NA^(c) po 5 2 1590 4.7 16402 16418 NA NA7.2 7.3 53.7 ^(a)Maximum observed concentration at first time point;^(b)First plasma collection time; ^(c)NA = not applicable.

Example 3: Compound 1 Single Dose Dog PK Study

A pharmacokinetic study of Compound 1 following a single intravenous ororal dose administration to male beagle dogs was conducted, the resultsof which are found in Table 4 and FIGS. 13-18.

TABLE 4 T_(max) C_(max) t_(1/2) AUC_(LAST) AUC_(inf) Cl V_(ss)MRT_(last) MRT_(inf) F Animal # (hr)^(a) (ng/ml) (hr)^(b) (hr · ng/ml)(hr · ng/ml) (ml/hr/kg) (ml/kg) (hr) (hr) (%) iv, 0.5 mg/kg 1 0.083 326NC 7233 NC NC NC NC NC NA 2 0.083 380 NC 7530 NC NC NC NC NC NA 3 0.250308 NC 6556 NC NC NC NC NC NA Mean 0.139 338 7106 NA SD 0.096 37 500 po,2 mg/kg 4 0.25 279 NC 7892 NC NC NC NC NC 27.8 5 1.00 293 NC 8155 NC NCNC NC NC 28.7 6 1.00 243 NC 8380 NC NC NC NC NC 29.5 Mean 0.75 272 814228.6 SD 0.43 26 244 0.9 ^(a)For the iv group, the first plasmacollection time is typically listed as the T_(max;) ^(b)Terminal phaseparameters could not be calculated because plasma levels did notdecrease steadily from the T_(max); NA = not applicable; NC = notcalculated.

Example 4: Compound 2 Single Dose Rat PK Study

A pharmacokinetic study of Compound 2 following a single intravenous ororal dose administration to male Sprague Dawley rats was conducted, theresults of which are found in Table 5 and FIGS. 19-24.

TABLE 5 Dose T_(max) C_(max) t_(1/2) AUC_(LAST) AUC_(inf) Cl V_(ss)MRT_(last) MRT_(inf) F Rat #^(a) (mg/kg) (hr)^(b) (ng/ml) (hr) (hr ·ng/ml) (hr · ng/ml) (ml/hr/kg) (ml/kg) (hr) (hr) (%)^(c) iv route 1 10.083 528 12.8 769 798 1254 10170 5.92 8.11 NA 2 2 0.083 1494 9.99 17441763 1134 4218 3.06 3.72 NA po route 4 5 1.00 160 10.77 1504 1548 NC NC9.22 10.77 35 5 5 2.00 189 10.29 2038 2125 NC NC 9.82 12.01 48 Mean 1.50175 10.53 1771 1837 NC NC 9.52 11.39 42 ^(a)Rat #3 died immediatelyafter dose of 2 mg/kg; Rat #1 was administered a lower dose, 1 mg/kg;^(b)For the iv group, the first plasma collection time is listed as theT_(max); ^(c)Bioavailability (F) was determined using AUC_(inf) fordetermined using 2 mg/kg (Rat #2); NA = not applicable.

Example 5: Compound 2 Single Dose Mouse PK Study

A pharmacokinetic study of Compound 2 following a single intravenous ororal dose administration to male CD-1 mice was conducted, the results ofwhich are found in Table 6 and FIGS. 25-31.

TABLE 6 Dose T_(max) C_(max) t_(1/2) AUC_(LAST) AUC_(inf) Cl V_(ss)MRT_(last) MRT_(inf) F Route (mg/kg) (hr) (ng/ml) (hr) (hr · ng/ml) (hr· ng/ml) (ml/hr/kg) (ml/kg) (hr) (hr) (%) iv 2 0.25 649 6.5 5667 5709350 2954 8.1 8.4 NA po 5 4 517 6.2 8721 8778 NA NA 9.7 10.0 61.6

Example 6: Compound 2 Mouse Efficacy Study for NASH

An efficacy study was conducted with Compound 2 in ob/ob mice, using twodifferent experimental designs, the results of which are found in FIGS.32A-38B. Mice in cohort 1 were untreated or dosed orally with compound 2(25 mg/kg) while being fed a high fat diet (HFD, FIG. 32A). Mice incohort 2 were first conditioned with a high fat diet, and then treatedwith a control vehicle, Compound 2 (50 mg/kg) or obeticholic acid (OCA,30 mg/kg). Mice treated with Compound 2 in both cohorts demonstrateddecreased levels of RBP4 (FIGS. 33A and 33B), improved plasma insulinlevels, and improved glucose tolerance relative to controls (FIGS.34A-35B). Western blot analysis of fat tissue was obtained from fouranimals in cohort 1. Animals in cohort 1 treated with compound 2 showedlower RBP4 expression levels relative to the untreated control (FIG.36). Animals in cohort 2 showed a reduction in NASH fibrosis scoresrelative to untreated controls, reflected as a decrease in the amount ofbridging fibrosis (FIGS. 37, 38A, 38B).

Example 7: Phase 1 Protocol for Human Clinical Study for Compounds 1 and2

Subjects.

The subject population consists of healthy volunteers.

Objectives.

Objects of the study are to characterize the systemic and hepatic safetyof single and multiple doses of Compound 1 or 2, characterize thepharmacokinetics (PK) of single and multiple doses of Compound 1 or 2,and determine effects of single and multiple doses of Compound 1 or 2 onserum levels of retinol binding protein 4 (RBP4), a pharmacodynamics(PD) marker.

Study Design and Duration.

The study is a randomized, double blind, placebo-controlled, sequentialsingle and multiple ascending dose study. There are 5 dose levels in thesingle and 5 dose levels in the multiple ascending dose components. Eachcohort consists of 8 subjects, 6 receiving compound 1 or 2 and 2receiving placebo. Consistent with NINDS policies, 3-5 subjects in eachcohort are female and efforts should be made to include diverse racesand ethnicity. All subjects participate in a screening period lasting upto 28 days, during which they are assessed for eligibility.

Single Ascending Dose Treatment Group.

Cohorts 1-3 reside in the research unit from Day −1 through Day 3;Cohorts 4 and 5 on Days −1 to 4. On Day −1 baseline safety and PDmarkers are obtained. Subjects receive a single oral dose on the morningof Day 1. Safety, PK and PD are obtained through Day 3 in early cohorts,though Day 4 in later. A phone call to ask about adverse events andconcomitant medications takes place on Day 6. Subjects return for anoutpatient visit on Day 8.

Multiple Ascending Dose Treatment Group.

Cohorts 1-3 reside in the research unit from Day −1 to Day 3; Cohorts 4and 5 from Day −1 to Day 4. Subjects receive the first oral dose on themorning of Day 1. Safety, PK and PD are obtained through Day 3 or 4, asappropriate, and subjects are discharged from the research unit withinvestigational product (IP) to take as an outpatient. Subjects returnfor outpatient visits on Days 6, 8, and 12. They are readmitted to theunit on the morning of Day 15 and receive the final oral dose in theresearch unit. Safety, PK and PD are collected until discharge on Day 17for Cohorts 1-3, day 18 for Cohorts 4 and 5. Subjects return for a lastsafety visit on Day 22. Specifics regarding safety, PK and PD collectionfor both SAD and MAD are described verbally in following sections, andpresented in tabular form in Tables 5-10.

Number of Subjects.

40 subjects are in the single dose ascending group, 40 subjects are inthe multiple dose ascending group, and there are 80 subjects total. Onlysubjects who discontinue prior to their first dose of IP are replaced.

Safety Evaluation.

Safety is evaluated by collecting adverse events, physical examination,Ocular examination (including slit lamp biomicroscopy, dilatedophthalmoscopy and intraocular pressure), Visual acuity, D-28 colorvision text, Visual fields, Night vision questionnaire (multiple doseonly), Vital signs (blood pressure, heart rate, temperature, respiratoryrate), Weight, CBC with differential and platelets, serum chemistry,urinalysis, and ECG.

Twelve lead ECG are performed following recommendations in ICH E14regarding evaluation of QTc prolongation in patients in early stageclinical trials. ECGs are performed in triplicate on Days 1, 2, 8, 15and 16. Visual acuity is measured using Early Treatment of DiabeticRetinopathy Study (ETDRS) Visual Acuity charts 1 and 2. The chart isplaced on an ETDRS light box which is hung at eye level on the wall orplaced on a stand. Room lighting is at office levels and uniform betweenthe subject and the light box. The distance from the patient's eyes tothe Visual Acuity Chart is 4.0 meters. If vision tests are performed onthe same day as an ERG, they are completed prior to pupil dilation.

Outcome Measures (PK).

PK sampling of plasma is conducted in all subjects (for example predose,0.5, 1, 1.5, 2, 3, 4, 8, 8, 10, 12, 16, 24, 36 and 48 hours post dose onDays 1-3 and 15-17; trough predose on other days; and times arefinalized based on toxicokinetics). Compound 1 or 2 concentrations aredetermined using a high-pressure liquid chromatography coupled with amass spectrometer(LC/MS/MS) method. The method is determined duringtoxicokinetic studies and then validated for human application.Validation includes determination of the limits of quantitation. Iftoxicokinetics show significant urinary excretion, then urine PK methodswould be added. If toxicokinetics show significant metabolites, thismethod would be added.

Outcome Measures (PD).

Serum RBP4 is measured using a validated commercial ELISA assay.Full-field ERG measurements are recorded after pupil dilation using 10%tropicamide and 30 minutes of dark adaptation at baseline and on Day 1(approximately 6 hours), Day 2 (24-36 hours postdose), and Day 4(highest dose cohorts only). Responses are obtained from both eyessimultaneously and include the International Society for ClinicalElectrocardiography of Vision (ISCEV) standard rod response (0.03cd/m²-seconds) and combined response (1.5 cd/m²-seconds) in the dark,and the 31-Hz flicker response (2.25 cd/m²-seconds) and 1-Hz coneresponse (2.25 cd/m²-seconds) in the presence of a backgroundillumination (34 cd/m²).

Inhibition of the visual cycle as evidenced by the delay in restorationof the ERG b-wave amplitude following the photobleach is measured. Aftera 10-minute exposure to a full-field bleaching light (556 cd/m2),recovery of the ERG is measured for 60 minutes at 10-minute intervals.

Investigational Product.

Compound 1 or 2 is provided as 50 and 200 mg capsules. Matching placebois provided as identical looking capsules. Instructions for shipping,storage and handling is provided in the protocol. The dose levels are50, 100, 150, 200 and 400 mg. Compound 1 or 2 is taken in the morning inthe fasting state, with 4-8 ounces of water, as needed.

Statistical Analysis.

All subjects who receive IP are included in the safety population. Allsubjects who receive IP and have at least one post-treatment sample ordetermination are included in the PK analysis population. Analysis is bytreatment assignment. Safety is evaluated by monitoring AEs, and bychange from baseline on examinations and laboratory studies. The AEs arecoded using the Medical Dictionary for Regulatory Activities (MedDRA)and summarized by system organ class (SOC) and preferred term, byseverity, by relationship to study drug and study procedure, and bystudy drug dose. ECG parameters analyzed include heart rate, PR, QRS,QT, QTcB and QTcF intervals. Analysis of other examinations arespecified in the protocol.

PK parameters are summarized using descriptive statistics (mean,standard deviation, coefficient of variation [CV], median, minimum, andmaximum) by treatment. Geometric means are determined for AUC_(0-inf),AUC_(0-t), and C_(max). The following PK parameters are determined:maximum observed plasma concentration (C_(max)) and time of the maximumobserved plasma concentration (T_(max)), obtained directly from the datawithout interpolation; the apparent terminal elimination rate constant(λ_(Z)), determined by log-linear regression of the terminal plasmaconcentrations; area under the plasma concentration-time curve from time0 to the time of the last measureable concentration (AUC_(0-t)),calculated by the linear trapezoidal method; apparent plasma terminalelimination half-life (t_(1/2)), calculated as 0.693/λ_(Z); area underthe plasma concentration-time curve from time 0 to infinity(AUC_(0-inf)) where AUC_(0-inf)=AUC_(0-t)+C_(t)/λ_(z) and C_(t) is thelast measureable concentration; and apparent total plasma clearance(CL/F); and apparent volume of distribution during the terminal phase(V_(Z)/F).

The following outcome measures are calculated for ERGs: Absolute darkadapted prebleach rod amplitude at each time point; dark adaptedprebleach rod amplitude at each time point as % baseline; recovery fromphotobleaching—% rod amplitude at 60 minutes recovery versus rodamplitude immediately prior to bleaching; and time to >90% recovery ofrod amplitude from photobleaching.

Example 8: Treatment of NASH in Humans

250 adults with symptoms associated with nonalcoholic steatohepatitis(NASH) are randomly assigned to receive compound 1 or 2, each at a dailydose of 50 mg, 100 mg, 150 mg, 200 mg, 400 mg, or placebo, for up to 6months. The primary outcome is an improvement in histologic features ofnonalcoholic steatohepatitis, as assessed with the use of a composite ofstandardized scores for one or more of steatosis, lobular inflammation,hepatocellular ballooning, cirrhosis, and fibrosis. The results areanalyzed following methods well known to the skilled artisan.

Example 9: Treatment of NAFLD and NASH in Humans

Subjects with NAFLD or NASH are treated with doses of either 50 or 100mg/day of compound 1 or 2 for 6 months. Subjects are permitted theirusual other medications (e.g. antidiabetic medications such as metforminor sulfonamides) but not glitazones, PPAR agonists, OCA, or similarmedications. The subjects are assessed before the study, and atintervals during the study, such as every 4 weeks during the study and 4weeks after the last dose of compound 1 or 2, for safety andpharmacodynamic evaluations.

MRIs of the subjects' livers are taken every 4 weeks during the studyand 4 weeks after completion of compound 1 or 2 dosing, to determinehepatic fat; and liver biopsies are taken before the study (to establishthe diagnosis) and 4 weeks after completion of compound 1 or 2 dosing.At each visit, after a 12-hour fast, blood is drawn and urine collected;and a standard metabolic panel, complete blood count, and standardurinalysis are performed. Blood is analyzed for total cholesterol,HDL-C, LDL-C, VLDL-C, TGs, apoB, and liver transaminases. The subjectsalso maintain health diaries, which are reviewed at each visit. Thesubjects show a dose-related improvement in their disease, as manifestedby, for example, MRI and liver biopsy.

Example 10: Treatment of Obesity in Humans

Overweight subjects are treated with doses of either 50 or 100 mg/day ofcompound 1 or 2 for 2 months. The subjects are not coffee drinkers orconsumers of any other form of caffeine. The subjects are not to alterany other behavioral parameter such as diet or exercise. The subjectsare assessed before the study, and at intervals during the study, suchas every 2 weeks during the study and 4 weeks after the last dose ofcompound 1 or 2, for safety and pharmacodynamic evaluations, and weightloss.

Example 11: Treatment of Type II Diabetes in Humans

Subjects diagnosed with type 2 diabetes mellitus are treated with dosesof either 50 or 100 mg/day of compound 1 or 2 for 4 months. The subjectsare not to alter any other behavioral parameter such as diet orexercise. The subjects are assessed before the study, and at intervalsduring the study, such as every 2 weeks during the study and 4 weeksafter the last dose of compound 1 or 2, for safety and pharmacodynamicevaluations, including markers of blood glucose, interstitial glucose,and insulin.

Example 12: Treatment of Diabetic Retinopathy in Humans

Adult patients aged between 35 and 65 years suffering from diabetesmellitus (insulin dependent or not insulin-dependent) and diabeticretinopathy (non-proliferative and proliferative diabetic retinopathy)are treated with either 100 or 200 mg/day of compound 1 or 2 for 4months. The subjects are not to alter any other behavioral parametersuch as diet or exercise. Patients submitted to previous treatment ofthe retinopathy with laser are excluded from the test. The subjects areassessed before the study, at intervals during the study, such as every2 weeks during the study, at the end of the treatment period, and 4weeks after the last dose of compound 1 or 2, for safety andpharmacodynamic evaluations. The evaluations include markers of bloodglucose, interstitial glucose, and insulin, as well as imaging includingfundus photography, optical coherence tomography, fluoroangiographicexamination, and retinography. The fluoroangiography and retinographyare carried out according to the standard methods and the photograms aregraduated by giving a score to the plasmatic exudation and to the hardexudates on the basis of the ERDRS Classification.

We claim:
 1. A method of treating a metabolic disease or disorder in asubject in need thereof, the method comprising administering to thesubject a composition comprising a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein: each R¹ is independently halogen, haloalkyl, or alkyl; R² is—H, —OH, or halogen; p is 0, 1, 2, 3, 4, or 5; and A has the structure:

wherein: α, β, χ, and δ are each independently absent or present, andwhen present each is a bond; X is N; Z₁ is S, O, or N; Z₂ is S, O, N, orNR³; R³ is H, C₁-C₄ alkyl, or oxetane; and B is a substituted orunsubstituted fused 5-, 6-, or 7-membered ring structure; and whereinthe metabolic disease or disorder is type II diabetes or diabeticretinopathy.
 2. The method of claim 1, wherein: when α is present, thenZ₁ and Z₂ are N, X is N, β is present, and χ and δ are absent.
 3. Themethod of claim 1, wherein A has the structure

wherein: n is 0, 1, or 2; α, β, χ, δ, ϵ, and ϕ are each independentlyabsent or present, and when present each is a bond; Z₁ is S, O, or N; Z₂is S, O, N or NR³, wherein R³ is H, C₁-C₄ alkyl, or oxetane; X is N; Y₁,Y₂, Y₃ and each occurrence of Y₄ are each independently CR⁴, C(R⁵)₂,NR⁶, O, N, SO₂, or —(C═O)—, wherein: each R⁴ is independently H,halogen, C₁-C₁₀ alkyl, C₁-C₁₀ cycloalkyl, —O(C₁-C₁₀ alkyl), —C(O)OH,—C(O)O(C₁-C₁₀ alkyl), —C(O)NH₂, —C(O)NH (C₁-C₄ alkyl), —C(O)N(C₁-C₄alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄ alkyl)₂, —SO₂NH(C₁-C₁₀alkyl), —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF₃; each R⁵ is independently Hor C₁-C₁₀ alkyl; and each R⁶ is independently H, C₁-C₁₀ alkyl, C₃-C₆cycloalkyl, —(C₁-C₁₀ alkyl)CF₃, —(C₁-C₁₀ alkyl)OCH₃, —(C₁-C₁₀alkyl)-halogen, —SO₂(C₁-C₁₀ alkyl), —SO₂(C₁-C₁₀ alkyl)-CF₃, —SO₂(C₁-C₁₀alkyl)OCH₃, —SO₂(C₁-C₁₀ alkyl)-halogen, —C(O)(C₁-C₁₀ alkyl),—C(O)(C₁-C₁₀ alkyl)CF₃, —C(O)(C₁-C₁₀ alkyl)OCH₃, —C(O)(C₁-C₁₀alkyl)-halogen, —C(O)NH(C₁-C₁₀ alkyl), —C(O)N(C₁-C₁₀ alkyl)₂, —(C₁-C₁₀alkyl)C(O)OH, —C(O)NH₂, or oxetane.
 4. The method of claim 1, wherein:when α is present, then Z₁ and Z₂ are N, X is N, β is present, and χ andδ are absent; when ϵ and ϕ are each present, then n=1, and each of Y₁,Y₂, Y₃, and Y₄, are independently —CR⁴— or N; or when ϵ and ϕ are eachabsent, then n=0, 1 or 2, each of Y₁, Y₂, Y₃, and each occurrence of Y₄are independently C(R⁵)₂, NR⁶, O, or SO₂.
 5. The method of claim 1,wherein: α, β, ϵ, and ϕ are present; χ and δ are absent; Z₁ is N; Z₂ isN; and X is N.
 6. The method of claim 1, wherein A has the structure:

wherein: Y₁, Y₂, Y₃ and Y₄ are each independently CR₄ or N; and each R⁴is independently H, halogen, C₁-C₁₀ alkyl, C₁-C₁₀ cycloalkyl, —O(C₁-C₁₀alkyl), —C(O)OH, —C(O)O(C₁-C₁₀ alkyl), —C(O)NH₂, —C(O)NH (C₁-C₄ alkyl),—C(O)N(C₁-C₄ alkyl)₂, —NHC(O)NH(C₁-C₁₀ alkyl), —NHC(O)N(C₁-C₄ alkyl)²,—SO₂NH(C₁-C₁₀ alkyl), —SO₂N(C₁-C₁₀ alkyl)₂, —CN, or —CF³.
 7. The methodof claim 1, wherein A has the structure

wherein: each R₄ is independently H, halogen, C₁-C₄ alkyl, C₃-C₆cycloalkyl, —O(C₁-C₄ alkyl), —CN, —CF₃, —C(O)OH, —C(O)NH₂, —C(O)N(CH₃)₂,—C(O)NHCH₃, or —NHC(O)N(CH₃)₂.
 8. The method of claim 1, wherein each R¹is independently F, Br, Cl, C₁₋₆ haloalkyl, or C₁₋₆ alkyl.
 9. The methodof claim 1, wherein each R¹ is independently F or CF₃.
 10. A method oftreating a metabolic disease or disorder in a subject in need thereof,the method comprising administering to the subject a compositioncomprising a therapeutically effective amount of a compound having thestructure:

or a pharmaceutically acceptable salt thereof; and wherein the metabolicdisease or disorder is type II diabetes or diabetic retinopathy.
 11. Amethod of treating a metabolic disease or disorder in a subject in needthereof, the method comprising administering to the subject acomposition comprising a therapeutically effective amount of a compoundhaving the structure:

or a pharmaceutically acceptable salt thereof; and wherein the metabolicdisease or disorder is type II diabetes or diabetic retinopathy.
 12. Themethod of claim 1, wherein the therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereofis up to 25 mg per day, up to 50 mg per day, up to 75 mg per day, up to100 mg per day, up to 150 mg per day, up to 200 mg per day, up to 400 mgper day, up to 600 mg per day, up to 800 mg per day, or up to 1000 mgper day.
 13. The method of claim 1, wherein 24 hours afteradministration of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, the serum or plasma levels of RBP4 are reducedby at least 50% from baseline.
 14. The method of claim 1, wherein 24hours after administration of a compound of Formula (I), or apharmaceutically acceptable salt thereof, the serum or plasma levels ofRBP4 are reduced by at least 1 mg/dL.
 15. The method of claim 1, whereinthe disease or disorder is type II diabetes.
 16. The method of claim 1,wherein the disease or disorder is diabetic retinopathy.
 17. The methodof claim 1, wherein the compound is administered to the subject orallyor intravenously.
 18. The method of claim 1, wherein the administrationis to treat an existing disease or disorder.
 19. The method of claim 1,wherein the administration is provided to reduce the risk of type IIdiabetes, its chronic complications, or its clinical symptoms.